Ischaemic episodes of less than 5 minutes produce preconditioning but not stunning in the isolated rat heart

The aim of the present study was to examine whether ischaemic episodes of less than 5 min could induce preconditioning or stunning in the isolated rat heart. Hearts were subjected to total global ischaemia of 1, 2 and 4 min followed by 10 min of reperfusion before an 18-min main ischaemic period and 30 min of reperfusion. The effects on physiology, purine metabolism and anaerobic glycolysis were compared with a control group subjected to the main ischaemia only. The brief ischaemic episodes did not produce stunning based on the recovery of left ventricular developed pressure (LVDP) and heart rate (HR) product during the first reperfusion. Preconditioning of 11–14% increased recovery of LVDP x HR during the second reperfusion was observed in the 1- and 4-min group. In the 2-min group a low repayment of flow debt during the first reperfusion was associated with a slightly reduced recovery of LVDP x HR compared to the other preconditioned groups during the second reperfusion. Only in the 4-min group was preconditioning associated with fewer breakdown products of the purine nucleotide pool (adenosine) and anaerobic glycolysis (lactate) in both tissue and effluate after the main ischaemia. Preconditioning (reflected in recovery of function) could be produced with ischaemic episodes of less than 5 min that did not produce stunning. Thus, stunning is probably not the primary cause of preconditioning.     

2,8-Dihydroxyadenine urolithiasis in a patient with considerable residual adenine phosphoribosyltransferase activity in cell extracts but with mutations in both copies of APRT

We have examined the mutational basis of adenine phosphoribosyltransferase (APRT, EC 2.4.2.7) deficiency (MIM 102600) in a patient of Polish origin who has been passing 2,8-dihydroxyadenine (DHA) stones since birth, but has considerable residual enzyme activity in lymphocyte extracts. The five exons and flanking regions of APRT were amplified by PCR and then sequenced. A single T insertion was identified at the intron 4 splice donor site (TGgtaa to TGgttaa:IVS4+2insT) in one allele from the proband, his mother, and brother. A G-to-T transversion in exon 5 (GTC-to-TTC:c.448G>T, V150F) was identified in the other allele, and this mutation was also present in one allele from the father and the paternal grandmother. Tru91 and AvaII digestions of PCR products spanning exons 4 and 5, respectively, confirmed the mutations. The mother was heterozygous for an intragenic TaqI site, but all other family members were homozygous for the presence of this site. IVS4+2insT, located on the allele containing the TaqI site, has been identified previously in several families from Europe, suggesting a founder effect, but the substitution in exon 5 is a novel mutation. IVS4+2insT is known to result in complete loss of enzyme activity, and our results suggest that V150F produces an enzyme that is nonfunctional in vivo but has considerable residual activity in vitro.     

Epitope mapping and characterization of a novel CD4-induced human monoclonal antibody capable of neutralizing primary HIV-1 strains

Human immunodeficiency virus (HIV-1) enters target cells by binding its gp120 exterior envelope glycoprotein to CD4 and one of the chemokine receptors, CCR5 or CXCR4. CD4-induced (CD4i) antibodies bind gp120 more efficiently after CD4 binding and block the interaction with the chemokine receptor. Examples of CD4i antibodies are limited, and the prototypes of the CD4i antibodies exhibit only weak neutralizing activity against primary, clinical HIV-1 isolates. Here we report the identification of a novel antibody, E51, that exhibits CD4-induced binding to gp120 and neutralizes primary HIV-1 more efficiently than the prototypic CD4i antibodies. The E51 antibody blocks the interaction of gp120-CD4 complexes with CCR5 and binds to a highly conserved, basic gp120 element composed of the beta 19-strand and surrounding structures. Thus, on primary HIV-1 isolates, this gp120 region, which has been previously implicated in chemokine receptor binding, is accessible to a subset of CD4i antibodies.     

Blood-retina barrier in acute retinal branch vein occlusion

Background: Extensive clinical studies on retinal branch vein occlusion have not yet been able to clarify its pathogenesis. A study designed to look at the associated blood-retina barrier changes may contribute to a better understanding of the different forms of evolution of this pathology. Methods: A prospective study was done in seven patients with recent large temporal branch vein occlusion. Vitreous fluorophotometry, fluorescein angiography and retinal colour photography were performed within the 1st week after the onset of symptoms, 1 week later, and at 12 and 24 weeks. Results: A more marked blood-retina barrier breakdown was found at 1, 2, 12 and 24 weeks in the eyes that later developed extensive capillary non-perfusion. Conclusions: Our results suggest that the breakdown of the blood-retina barrier may play an important role in the subsequent development of retinal nonperfusion in eyes with large branch vein occlusion. We postulate that the eyes that will present later extensive capillary nonperfusion develop, from the initial stages of the disease, a progressive ischaemic capillaropathy characterized by blood-retina barrier breakdown. Retinal pigment epithelium degeneration and arterial lumen narrowing, secondary to the vein obstruction, may help to increase and perpetuate the blood-retina barrier breakdown during the first 6 months after the occlusion.     

Novel imaging techniques for diabetic macular edema

Retinal edema should be defined as any increase of water of the retinal tissue resulting in an increase in its volume. It may be of cytotoxic or vasogenic origin. Development of vasogenic macular edema is dependent on a series of factors such as blood pressure, blood-retinal barrier permeability, retinal cell damage, retinal tissue osmotic pressure and retinal tissue compliance. Objective measurements of retinal thickness are now possible using the Retinal Thickness Analyser. Localised measurements of blood-retinal barrier permeability may also be obtained using the Retinal Leakage Analyser, a modified confocal scanning laser fluorometer, while obtaining simultaneously angiographic images of the choroid and retina. These new imaging techniques show that cytotoxic and vasogenic retinal edema may occur independently in the early stages of diabetic retinopathy. These findings offer new perpectives for designing novel therapeutic strategies. This revised version was published online in July 2006 with corrections to the Cover Date.     

Tedisamil Attenuates Ventricular Fibrillation in a Conscious Canine Model of Sudden Cardiac Death

BACKGROUND: The electrophysiologic and antifibrillatory properties of tedisamil (KC-8857;3,7-di-(cyclopropylmethyl)-9,9-tetramethylene-3,7-diazabicyclo[3.3.1]-nonane dihydrochloride) were studied in a conscious canine model of sudden cardiac death. METHODS AND RESULTS: Three to five days after surgically induced myocardial infarction (2-hour occlusion of the left anterior descending coronary artery), animals were subjected to programmed electrical stimulation to identify those at risk for ischemia-induced ventricular fibrillation. Sixty minutes after tedisamil (10 mg/kg, administered orally) PES was repeated. Tedisamil increased the ventricular effective refractory period from 106 +/- 6 to 134 +/- 7 ms (P <.05) compared to placebo treatment, which did not alter the ERP (123 +/- 6 to 116 +/- 5 ms). Tedisamil prolonged the QTc interval, from a predrug value of 308 +/- 14 to 327 +/- 14 ms, postdrug. The extent of the surgically induced anterior wall myocardial infarct did not differ between groups, tedisamil, 29 +/- 2%, and placebo, 28 +/- 2% of the left ventricle. CONCLUSIONS: Tedisamil conferred protection against ischemia induced ventricular fibrillation; 7 of 10 tedisamil-treated dogs survived, compared to 4 of 14 surviving in the vehicle treated group (P <.05). Although we observed instances of vomiting and/or diarrhea in several dogs after a single oral administration of tedisamil, the data indicate that oral administration of tedisamil provides protection from ischemia-induced ventricular fibrillation in the postinfarcted conscious canine. The mechanism by which tedisamil achieves its antifibrillatory effect may be related to its ability to prolong the ERP of the ventricular myocardium without altering ventricular conduction velocity.     

Aberrant crypt focus promotion and glucose intolerance: correlation in the rat across diets differing in fat, n-3 fatty acids and energy

McKeown-Eyssen (Cancer Epidemiol. Biomarkers Prevent., 3, 687-695, 1994) and Giovannucci (Cancer Causes Control, 6, 164-179, 1995), noting the striking similarity in lifestyle risk factors for colorectal cancer and insulin resistance, proposed that the hyperinsulinemia, glycemia and hypertriglyceridemia associated with insulin resistance promotes colon cancer. To compare the effect of diet on colon cancer promotion and insulin resistance in the F344 rat, we assessed the effect of fat, n-3 fatty acids and energy in pairwise comparisons on average size of aberrant crypt foci (ACF) and on glucose intolerance in the same animals in a single experiment. Diets high in fat and energy increased and diets with increased n-3 fatty acids and calorie restriction decreased both ACF growth and glucose intolerance compared with control diets. The measures of promotion of colon cancer and insulin resistance were strongly correlated (n = 98, r = 0.67, P < 0.001). In addition, both were highly correlated with daily energy intake (r = 0.62 and 0.66) and were also correlated with basal (post-prandial) insulin, glucose and triglycerides (r = 0.31-0.53, P < 0.01). We concluded that ACF growth and glucose intolerance are correlated for a wide range of diets and that increased circulating energy (glucose and triglycerides) may lead to both colon cancer promotion and insulin resistance.      

Coexistence of benign phyllodes tumor and invasive ductal carcinoma in distinct breasts: case report

This report describes a rare case of coexistence of benign phyllodes tumor, which measured 9 cm in the right breast, and invasive ductal carcinoma of 6 cm in the left breast, synchronous and independent, in a 66-year-old patient. The patient underwent a bilateral mastectomy due to the size of both lesions. Such situations are rare and usually refer to the occurrence of ductal or lobular carcinoma in situ when associated with malignant phyllodes tumors, and more often in ipsilateral breast or intra-lesional.